Alcohol addiction is a major issue in public health; however the impact of current pharmacotherapies is modest. Other addictive disorders, including the abuse of narcotics and dependence upon tobacco products, also severely burden health care systems due to high prevalence and lack of availability of fully effective treatments. Thus, the identification of the brain mechanisms responsible for addictions and the development of treatments for curbing various addictions are important health care issues.
Nociceptin, a peptide of 17 amino acid residues, is a recently discovered endogenous ligand for what has been termed the orphan receptor opioid receptor-like 1 (ORL1), now referred to as the nociceptin receptor (NOP), a G-protein coupled receptor. Despite the high sequence homology between the NOP and the opioid receptors, most opioids lack high affinity for NOP. Further, the actions of nociceptin, an anti-analgesic, are not antagonized by opioid antagonists such as naloxone. Nociceptin itself resembles certain opioid peptides such as β-endorphin in its amino acid sequence, but it does not significantly bind to the classic opioid receptors. It is believed to modulate the perception of pain in the central nervous system, inter alia.
The nociceptin receptor (NOP) has been identified as a potential target for therapies addressing issues of alcohol and drug addiction, including addiction to widely-abused substances such as cocaine, heroin, amphetamines, and opiates such as morphine and oxycodone. Studies using nociceptin receptor modulators such as Ro-64-6198 have shown promise in treating alcohol addiction in relevant animal models, although to date no compounds of sufficient selectivity for NOP over opioid receptors and other GPCRs have been identified for advancement to clinical trials. Modulators of the classic opioid receptors, including the μ-opioid receptor (MOP) and the κ-opioid receptor (KOP), have found use in treating numerous malconditions. Certain compounds that modulate NOP also modulate these classic opioid receptors. NOP agonists or antagonists that are largely selective vs. MOP and KOP may have therapeutic advantages over less selective compounds. NOP-selective agonists have been suggested as anxiolytic agents lacking sedative side effects. Such compounds might effectively treat anxiety disorders such as post-traumatic stress syndrome, phobias, and compulsive disorders. Such compounds might also be used in the treatment of other CNS conditions such as cough, sleep disorders, and migraine. NOP-selective antagonists have been suggested for treatment of pain, depression, and neurodegenerative diseases, such as Parkinson's disease.